Effect of Gefapixant (MK-7264/AF-219) on Cough Reflex Sensitivity in Healthy and Chronic Cough Participants (MK-7264-014)

NCT02476890 | Completed Phase 2 Results FDA Drug

• 4 other identifiers: 7264-014MK-7264-014AF-219-0142015-002034-47
• Study Type: interventional
• Target: 36
• Locations: 0 countries
• Sites: N/A

Brief Summary

The primary objective of this study was to assess the effect of a single dose of gefapixant 100 mg on cough reflex sensitivity to various challenge agents (capsaicin, citric acid, adenosine triphosphate \[ATP\], and distilled water) in healthy and chronic cough participants.

Conditions

Refractory Chronic Cough

Outcome Measures

Primary Outcomes (4)

• Cough Reflex Sensitivity to Capsaicin in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

  The concentration of capsaicin inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of capsaicin for cough challenge were 0.3 micromoles (µM), 1 µM, 3 µM, 10 µM, 30 µM, 100 µM, 300 µM, and 1000 µM. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of capsaicin with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

  Average of 1, 3, and 5 hours post-dose

• Cough Reflex Sensitivity to Citric Acid in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

  The concentration of citric acid inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of citric acid for cough challenge were 1 millimoles (mM), 3 mM, 10 mM, 30 mM, 100 mM, 300 mM, 1 M, and 3 M. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of citric acid with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

  Average of 1, 3, and 5 hours post-dose

• Cough Reflex Sensitivity to ATP in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

  The concentration of ATP inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of ATP for cough challenge were 0.1 mM, 0.3 mM, 1 mM, 3 mM, 10 mM, 30 mM, 100 mM, and 300 mM. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of ATP with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

  Average of 1, 3, and 5 hours post-dose

• Cough Reflex Sensitivity to Distilled Water in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

  The concentration of distilled water inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of distilled water for cough challenge were 20%, 40%, 60%, 80%, and 100%. The Measure Type is least-squares mean in natural log scale. The number of coughs generated in 1 minute of exposure was recorded. The challenge agent was prepared by dilution of distilled water with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

  Average of 1, 3, and 5 hours post-dose

Secondary Outcomes (5)

• Change From Baseline in Cough Severity Visual Analogue Scale (VAS) After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

  Baseline and one hour after the final cough challenge on treatment days

• Change From Baseline in Urge to Cough VAS After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

  Baseline and one hour after final cough challenge on treatment days

• Change From Baseline in Cough Frequency After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

  Baseline and for 24 hours after cough challenge on treatment days

• Percentage of Participants Who Experienced One or More Adverse Events During Study Treatment and Follow up

  Up to Day 18

• Percentage of Participants Who Discontinued From the Study Due to an Adverse Event

  Up to Day 4

Study Arms (4)

Placebo then gefapixant 100 mg/Healthy (Sequence A)

EXPERIMENTAL

Healthy participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of gefapixant 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 \& 2.

Drug: Gefapixant 100 mg; Drug: Placebo

Gefapixant 100 mg then placebo/Healthy (Sequence B)

EXPERIMENTAL

Healthy participants in Sequence B received a single dose of gefapixant 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 \& 2.

Drug: Gefapixant 100 mg; Drug: Placebo

Placebo then gefapixant 100 mg/Chronic Cough (Sequence A)

EXPERIMENTAL

Chronic Cough participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of gefapixant 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 \& 2.

Drug: Gefapixant 100 mg; Drug: Placebo

Gefapixant 100 mg then placebo/Chronic Cough (Sequence B)

EXPERIMENTAL

Chronic Cough participants in Sequence B received a single dose of gefapixant 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 \& 2.

Drug: Gefapixant 100 mg; Drug: Placebo

Interventions

Gefapixant 100 mg DRUG

Gefapixant 100 mg (2 x 50 mg tablets), administered orally as a single dose in treatment Period 1 or treatment Period 2

Also known as: MK-7264, AF-219

Gefapixant 100 mg then placebo/Chronic Cough (Sequence B); Gefapixant 100 mg then placebo/Healthy (Sequence B); Placebo then gefapixant 100 mg/Chronic Cough (Sequence A); Placebo then gefapixant 100 mg/Healthy (Sequence A)

Placebo DRUG

Placebo (two tablets matching gefapixant 50 mg), administered orally as a single dose in treatment Period 1 or treatment Period 2

Gefapixant 100 mg then placebo/Chronic Cough (Sequence B); Gefapixant 100 mg then placebo/Healthy (Sequence B); Placebo then gefapixant 100 mg/Chronic Cough (Sequence A); Placebo then gefapixant 100 mg/Healthy (Sequence A)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have provided written informed voluntary consent;
• Be able to speak, read, and understand English;
• Be males or females, of any race, between 18 and 80 years of age, inclusive;
• Have a body mass index (BMI) \>= 18 and \< 35 kg/m\^2;
• Be in good general health with no clinically relevant abnormalities based on the medical history, physical examination, clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis), and 12 lead electrocardiogram;
• Be non-smokers for at least 5 years;
• If a female of child-bearing potential (I. e., have not undergone a hysterectomy or bilateral oophorectomy) or not post-menopausal (defined as no menses for at least 12 months), agree to use 2 forms of acceptable birth control; or if a male, they and/or their partner of child-bearing potential agree to use 2 forms of acceptable birth control;
• Be able to communicate effectively with the Investigator and other study center personnel and agree to comply with the study procedures and restrictions.
• Subjects with chronic cough must have treatment-refractory chronic cough for at least one year, with no objective evidence of an underlying trigger (e. g., asthma)

You may not qualify if:

• History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0);
• Have acute worsening of asthma;
• Do not cough during the ATP or Capsaicin or Citric acid challenge at Screening or only cough twice at the two highest concentrations of the test solution;
• History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including subjects with \<3 excised basal cell carcinomas);
• History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years;
• Clinically significant abnormal electrocardiogram (ECG) at Screening;
• Significantly abnormal laboratory tests at Screening;
• Pregnant or breastfeeding;
• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the Investigator or Sponsor, would make the subject inappropriate for entry into this trial.

Sponsors & Collaborators

• Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA): lead

Related Publications (1)

• Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, Thompson R, Thackray-Nocera S, Wright C. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019 Jul 4;54(1):1900439. doi: 10.1183/13993003.00439-2019. Print 2019 Jul.

  PMID: 31023843 RESULT

MeSH Terms

Conditions

Chronic Cough

Interventions

Gefapixant

Condition Hierarchy (Ancestors)

Cough; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Chronic cough and healthy participants were randomly assigned to receive gefapixant and placebo in one of two treatment sequences: Sequence A (placebo in treatment period 1, then gefapixant in treatment period 2) or Sequence B (gefapixant in treatment period 1, then placebo in treatment period 2). There was at least a 48-hour washout between the treatment periods. Daytime cough monitoring was performed in chronic cough participants only.

Study Record Dates

• First Submitted: June 15, 2015
• First Posted: June 22, 2015
• Study Start: October 28, 2015
• Primary Completion: October 20, 2016
• Study Completion: October 20, 2016
• Last Updated: June 18, 2019
• Results First Posted: February 15, 2018

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share